Anti-Angiogenetic Agents from the Sea: A New Potential Preventive and Therapeutic Wave?

Angiogenesis, generation of novel blood vessels from pre-existing ones, is a prerequisite for the physiological expansion, reparation, and functioning of body tissues and systems. However, it is also involved in some pathological inflammatory situations, such as oncologic and chronic degenerative disorders. The correct angiogenesis and neo-vascular response also accompanies wound healing, interaction with biocompatible materials, and tissue regeneration. In this respect, natural products deriving from terrestrial and marine plants/organisms may prevent and even cure various angiogenesis-dependent disorders. Bioactive natural compounds with antioxidant and anti-inflammatory activities could concur to maintain adequate vascularization and endothelial functions and inhibit angiogenesis, thus controlling tumor development. This review aims to illustrate the role of some marine-derived compounds as anti-angiogenetic agents.

Assessment of Body Composition in Oncologic Patients: Experimental Survey on the Role of Bioimpedentiometric Analysis.

Overall survival of oncologic patients is strongly influenced by the incidence of malnutrition, with subsequent loss of muscle mass until sarcopenia. In this respect, the assessment of body composition has a pivotal role in order to manage the clinical consequences of muscle loss. AIM: This study focuses on the body composition assessment in oncologic patients, following a diet plan in order to detect and contrast neoplastic cachexia. MATERIALS AND METHOD: 35 oncologic patients were enrolled and divided into two groups: 24 responders (R) and 11 non-responders (NR). Anthropometric data were collected and body composition was assessed through bioimpedentiometry. All patients received an individualized normocaloric diet. Energetic content was assigned on the basis of individual basal metabolic rate estimated by BIA. All patients were revaluated by anthropometry and bioimpedentiometry 3 and 6 months thereafter. RESULTS: Comparing the two male groups R and NR after 6 months, the former maintained almost the same confidence interval, unlike the latter whose interval increased, indicating a light worsening both of body composition and of clinical conditions. Furthermore, in the same male responder group, an improvement of the phase angle (PhA), a positive prognostic factor, was found, with an average weight loss between 2,6 - 3 kg of fat mass (FM). Besides, data show how the R female group maintained the confidence interval unlike the NR female group, whose confidence interval remarkably increased, therefore indicating an important alteration of body composition and subsequently a clinical conditions worsening. Finally, comparing the NR male group with the NR female group after 6 months, a remarkable worsening of body composition (marker of tissue decay and damage) could be noticed in the latter group. CONCLUSION: After 6 months, NR patients show worse results (both in the body composition and in the clinical conditions) compared to the responders, with particularly worse results in females, probably because of a genetically determined sex-related smaller muscle cells and inferior muscular strength. A multidimensional assessment of oncologic patient is necessary, with a special attention to nutritional evaluation and body composition monitoring, in order to avoid malnutrition and subsequent further clinical worsening.

Impact of chocolate on the cardiovascular health.

The antioxidants such as polyphenols, especially flavonols, present in large quantitites in cocoa, cause vasodilation, modulate inflammatory markers and cardiovascular health, and possess a range of protective cardiovascular effects. On the other hand, overconsumption of chocolate can lead to tachyarrhythmias, supraventricular tachycardia, atrial fibrillation, ventricular tachycardia and ventricular fibrillation due to its caffeine content. This review describes both the cardioprotective and adverse effects of chocolate and its constituents.

Silibinin Restores NAD⁺ Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver.

Nicotinamide adenine dinucleotide (NAD⁺) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5'-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NAD⁺/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks. HepG2 cells were treated with 0.25 mM palmitate for 24 h with silibinin 25 µM or vehicle. HFD and palmitate administration led to oxidative stress, poly-(ADP-ribose)-polymerase (PARP) activation, NAD⁺ consumption, and lower SIRT1 activity. In mice fed the HFD, and in HepG2 treated with palmitate, we consistently observed lower levels of phospho-AMPKThr172 and phospho-acetyl-CoA carboxylaseSer79 and higher levels of nuclear sterol regulatory element-binding protein 1 activity, indicating de novo lipogenesis. Treatment of mice and HepG2 with silibinin abolished oxidative stress, and inhibited PARP activation thus restoring the NAD⁺ pool. In agreement with preserved NAD⁺ levels, SIRT1 activity and AMPK phosphorylation returned to control levels in mice and HepG2. Our results further indicate silibinin as a promising molecule for the treatment of NAFLD.

A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations.

SCOPE: To summarize available evidence on the association between dietary flavonoid as well as lignan intake and cancer risk in observational studies. METHODS AND RESULTS: A systematic search on electronic databases of all English language case-control and prospective studies published up to June 2016 was performed. Risk ratios (RRs) and 95% confidence intervals were calculated by random-effects model separately by study design. Heterogeneity and publication bias were tested. Out of the 143 studies included, meta-analyses of prospective studies showed isoflavones significantly associated with decreased risk of lung and stomach cancers and nearly significant breast and colorectal cancers; total flavonoids showed nonsignificant decreased risk of breast cancer. Meta-analyses of case-control studies showed: total and/or individual classes of flavonoids associated with upper aero-digestive tract, colorectal, breast, and lung cancers; isoflavones with ovarian, breast, and colorectal cancers, endometrial and lung cancers. CONCLUSIONS: Most evidence reported in previous meta-analyses was driven by case-control studies. Overall results may be promising but are inconclusive. Further prospective cohorts assessing dietary polyphenol exposure and studies using other methods to evaluate exposure (i.e. markers of consumption, metabolism, excretion) are needed to confirm and determine consumption levels required to achieve health benefits.

Novel Therapeutic Strategies Against Cancer: Marine-derived Drugs May Be the Answer?

Marine ecosystem represents a wide and untapped reservoir of biologically active metabolites. Most of the sponges, seaweeds, crustaceans, fish species and their associated microorganisms have evolved chemical means in order to defend themselves against predation and to survive in the complex marine environment. Such chemical and biological adaptation produced many bioactive substances with beneficial effects on human health, including potential anticancer agents. With further exploration of sea and ocean environment, several marine bioactives have been identified with promising anticancer activity. More than one hundred novel bioactive compounds with antitumor activity and their synthetic derivative substances displayed in vitro cytotoxic property on neoplastic cell lines and are currently gaining great attention for further evaluations and in vivo applications. This review highlights novel marine molecules and compounds which have been able to inhibit different cancer species in the recent years and aims to describe research on new natural antineoplastic agents obtained from sea world.

Resveratrol and anti-atherogenic effects.

The role of inflammation and oxidative stress in atherosclerosis development has been increasingly well recognized over the past decade. Inflammation has a significant role at all stages of atherosclerosis, including initiation, progression and plaque formation. Resveratrol is a naturally occurring polyphenolic compound found in grape products, berry fruits and red wine. Its ability to behave therapeutically as a component of red wine has attracted wide attention. Accumulating evidence suggests that it is a highly pleiotropic molecule that modulates numerous targets and molecular functions. Epidemiological studies indicate that the Mediterranean diet, rich in resveratrol, is associated with a reduced risk of atherosclerosis. Resveratrol is believed to decrease circulating low-density lipoprotein cholesterol levels, reduce cardiovascular disease risk; it reduces lipid peroxidation, platelet aggregation and oxidative stress. Resveratrol is considered a safe compound, since no significant toxic effects have been demonstrated after administration of a broad range of concentrations, and an effective anti-atherogenic agent.

Oxidative stress and body composition in prostate cancer and benign prostatic hyperplasia patients.

OBJECTIVE: To investigate the role of body composition and oxidative stress measured by total thiol groups (TTG) levels in prostate specimens of patients affected by benign prostatic hyperplasia (BPH) or prostate cancer (PCa). PATIENTS AND METHODS: From January 2011 to January 2013, a cohort of 150 consecutive male patients who underwent first prostate biopsy were enrolled. Twelve-core needle biopsy was performed as standard procedure, while twelve more needle tissue cores matched with the previous group were also collected for glutathione determination. After definitive diagnosis, measurement of glutathione was performed in the correspondent one matched prostatic sample where PCa or BPH were identified. A day after the prostatic biopsy, body composition was estimated by air plethysmography (BOD POD®). RESULTS: A significant difference of TTG was observed in BPH and PCa patients; 34 nanomole (nmol) reagent sulfihydrylc (RSH)/ mg protein vs. 1.1 nmol RSH/ mg protein respectively (p<0.05). In BPH patients, a negative correlation was found between TTG and age (r=-0.46; p<0.05), while, in PCa patients, a positive correlation was observed between TTG and fat mass (FM) (r=0.76; p<0.01) and waist circumference (WC) (r=0.49; p<0.05). Multivariate linear regression analysis showed TTG to be negatively associated with age (ß-coefficient=-0.4; p<0.05) in BPH patients and positively with FM (ß-coefficient=3.4; p<0.01) and WC (ß-coefficient=2.7; p<0.05) in PCa patients. CONCLUSION: Aging determines a progressive reduction of TTG in BPH patients, while in PCa subjects glutathione concentrations are significantly lower and FM and WC are associated with an unbalance of its levels.

Marine bioactives and potential application in sports.

An enriched diet with antioxidants, such as vitamin E, vitamin C, ß-carotene and phenolic compounds, has always been suggested to improve oxidative stress, preventing related diseases. In this respect, marine natural product (MNP), such as COX inhibitors, marine steroids, molecules interfering with factors involved in the modulation of gene expression (such as NF-κB), macrolides, many antioxidant agents, thermogenic substances and even substances that could help the immune system and that result in the protection of cartilage, have been recently gaining attention. The marine world represents a reserve of bioactive ingredients, with considerable potential as functional food. Substances, such as chitin, chitosan, n-3 oils, carotenoids, vitamins, minerals and bioactive peptides, can provide several health benefits, such as the reduction of cardiovascular diseases, anti-inflammatory and anticarcinogenic activities. In addition, new marine bioactive substances with potential anti-inflammatory, antioxidant and thermogenic capacity may provide health benefits and performance improvement, especially in those who practice physical activity, because of their increased free radical and Reacting Oxygen Species (ROS) production during exercise, and, particularly, in athletes. The aim of this review is to examine the potential pharmacological properties and application of many marine bioactive substances in sports.

ADMA/SDMA in elderly subjects with asymptomatic carotid atherosclerosis: values and site-specific association.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor known as a mediator of endothelial dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. We assessed the relationship between ADMA values and site-specific association of asymptomatic carotid atherosclerosis (intima-media thickness (CIMT) and plaque) in elderly subjects. One hundred and eighty subjects underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and carotid ultrasound investigation (CUI). All subjects had no acute or chronic symptoms of carotid atherosclerosis. Statistical analyses showed that high plasma levels of ADMA/SDMA were positively correlated to carotid atherosclerosis (CIMT and plaque) (p<0.001), with significant site-specific association. Total cholesterol, low density lipoprotein cholesterol, triglycerides and C-reactive protein plasma concentrations were significantly associated with asymptomatic carotid atherosclerosis (p<0.001). High serum concentrations of ADMA and SDMA were associated with carotid atherosclerotic lesions as measured by CIMT ad plaque and may represent a new marker of asymptomatic carotid atherosclerosis in elderly subjects.

Role of dietary and endogenous antioxidants in diabetes.

Diabetes affects different people of all ages, race, and sex. This is a condition characterized by a state of chronic hyperglycaemia that leads to an increase of intracellular oxidative stress linked to the overproduction of free radicals. In the present review, we focus our attention on the molecular mechanisms leading to oxidative stress-mediates complications with particular regard to central nervous system (CNS). Furthermore, the present review reports the effects of different kind of antioxidants with enzymatic and nonenzymatic action that may significantly decrease the intracellular free radicals' overproduction and prevents the hyperglycaemia-mediated complications.

Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases.

SIGNIFICANCE: Many physiological effects of natural antioxidants, their extracts or their major active components, have been reported in recent decades. Most of these compounds are characterized by a phenolic structure, similar to that of α-tocopherol, and present antioxidant properties that have been demonstrated both in vitro and in vivo. Polyphenols may increase the capacity of endogenous antioxidant defenses and modulate the cellular redox state. Such effects may have wide-ranging consequences for cellular growth and differentiation. CRITICAL ISSUES: The majority of in vitro and in vivo studies conducted so far have attributed the protective effect of bioactive polyphenols to their chemical reactivity toward free radicals and their capacity to prevent the oxidation of important intracellular components. One possible protective molecular mechanism of polyphenols is nuclear factor erythroid 2-related factor (Nrf2) activation, which in turn regulates a number of detoxification enzymes. RECENT ADVANCES: Among the latter, the heme oxygenase-1 (HO-1) pathway is likely to contribute to the established and powerful antioxidant/anti-inflammatory properties of polyphenols. In this context, it is interesting to note that induction of HO-1 expression by means of natural compounds contributes to prevention of cardiovascular diseases in various experimental models. FUTURE DIRECTIONS: The focus of this review is on the role of natural HO-1 inducers as a potential therapeutic strategy to protect the cardiovascular system against various stressors in several pathological conditions.

Effect of Treatment with Cyanidin-3-O-ß-D-Glucoside on Rat Ischemic/Reperfusion Brain Damage.

This study investigated the effect of cyanidin-3-O-ß-glucoside on an experimental model of partial/transient cerebral ischemia in the rats in order to verify the effectiveness of both pre- and posttreatments. Cyanidin-3-O-ß-glucoside-pretreated rats were injected with 10 mg/Kg i.p. 1 h before the induction of cerebral ischemia; in posttreated rats, the same dosage was injected during reperfusion (30 min after restoring blood flow). Cerebral ischemia was induced by bilateral clamping of common carotid arteries for 20 min. Ischemic rats were sacrificed immediately after 20 min ischemia; postischemic reperfused animals were sacrificed after 3 or 24 h of restoring blood flow. Results showed that treatment with cyanidin increased the levels of nonproteic thiol groups after 24 h of postischemic reperfusion, significantly reduced the lipid hydroperoxides, and increased the expression of heme oxygenase and γ-glutamyl cysteine synthase; a significant reduction in the expression of neuronal and inducible nitric oxide synthases and the equally significant increase in the endothelial isoform were observed. Significant modifications were also detected in enzymes involved in metabolism of endogenous inhibitors of nitric oxide. Most of the effects were observed with both pre- and posttreatments with cyanidin-3-O-ß-glucoside suggesting a role of anthocyanin in both prevention and treatment of postischemic reperfusion brain damage.

Dimethylarginine dimethylaminohydrolase/nitric oxide synthase pathway in liver and kidney: protective effect of cyanidin 3-O-ß-D-glucoside on ochratoxin-A toxicity.

The aim of the present study was to evaluate the effect of long-term cyanidin 3-O-ß-D-glucoside (C3G) and/or Ochratoxin A (OTA)-exposure on dimethylarginine dimethylamino hydrolase/nitric oxide synthase (DDAH/NOS) pathway in rats. The experiments were performed in rats supplemented with C3G (1 g/kg feed), OTA (200 ppb), and OTA + C3G. After 4 weeks of daily treatment, liver and kidneys were processed for eNOS, iNOS and DDAH-1 Western blotting, nitrite levels evaluation and DDAH activity determination. Results show that OTA is able to induce iNOS both in kidney and liver, whereas OTA is able to induce eNOS and DDAH-1 overexpression and DDAH activation only in kidney, resulting in increased nitrite levels. In kidney of OTA + C3G fed rats, iNOS, eNOS and DDAH-1 expression were less pronounced compared with those observed in the OTA-treated group. Coherent with the decreased iNOS, eNOS and DDAH-1 expression a decrease in nitrite levels and DDAH activity was observed in the OTA + C3G group. Results demonstrate that C3G is able to counteract the deleterious effects of chronic consumption of OTA and also suggest a possible involvement of iNOS-eNOS-DDAH impairment in OTA nephrocarcinogenity.

Marine bioactives: pharmacological properties and potential applications against inflammatory diseases.

Inflammation is a hot topic in medical research, because it plays a key role in inflammatory diseases: rheumatoid arthritis (RA) and other forms of arthritis, diabetes, heart diseases, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, allergies, asthma, even cancer and many others. Over the past few decades, it was realized that the process of inflammation is virtually the same in different disorders, and a better understanding of inflammation may lead to better treatments for numerous diseases. Inflammation is the activation of the immune system in response to infection, irritation, or injury, with an influx of white blood cells, redness, heat, swelling, pain, and dysfunction of the organs involved. Although the pathophysiological basis of these conditions is not yet fully understood, reactive oxygen species (ROS) have often been implicated in their pathogenesis. In fact, in inflammatory diseases the antioxidant defense system is compromised, as evidenced by increased markers of oxidative stress, and decreased levels of protective antioxidant enzymes in patients with rheumatoid arthritis (RA). An enriched diet containing antioxidants, such as vitamin E, vitamin C, ß-carotene and phenolic substances, has been suggested to improve symptoms by reducing disease-related oxidative stress. In this respect, the marine world represents a largely untapped reserve of bioactive ingredients, and considerable potential exists for exploitation of these bioactives as functional food ingredients. Substances such as n-3 oils, carotenoids, vitamins, minerals and peptides provide a myriad of health benefits, including reduction of cardiovascular diseases, anticarcinogenic and anti-inflammatory activities. New marine bioactives are recently gaining attention, since they could be helpful in combating chronic inflammatory degenerative conditions. The aim of this review is to examine the published studies concerning the potential pharmacological properties and application of many marine bioactives against inflammatory diseases.

Fucoxantin: a treasure from the sea.

The World Health Organization (WHO) estimates that 2.3 billion people will be overweight and 700 million obese in 2015. The reasons for this disastrous trend are attributed to the global tendency toward the reduced magnitude of exercise and physical activity and the increased dietary intake of fats, sugars and calories with reduced amount of vitamins and minerals. To prevent life-style-related diseases, like Metabolic Syndrome (MS), researchers' attention is increasingly focusing on some of the so called "functional foods" which may be useful for their prevention and treatment. One of these functional ingredients is fucoxanthin (FX), a characteristic carotenoid present in edible brown seaweeds, such as Undaria pinnatifida (Wakame), Hijikia fusiformis (Hijiki), Laminaria japonica (Ma-Kombu) and Sargassum fulvellum. The increasing popularity of this molecule is certainly due to its anti-obesity effect, primarily detected by murine studies. These works revealed FX mediated induction of uncoupling protein-1 (UCP-1) in abdominal white adipose tissue (WAT) mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Beyond this important role, in recent studies FX has shown a great antioxidant activity, anti-cancer, anti-diabetic and anti-photoaging properties. The aim of this review is to highlight the main effects of FX on human health.

Antiproliferative effect of oleuropein in prostate cell lines.

Currently, there is increasing interest in the in vivo protective effects of natural antioxidants found in dietary plants against oxidative damage caused by free radical species. Oxidative stress has been invoked as a causative agent in cancer and epidemiological data suggest that the consumption of fruits and vegetables may be associated with a lower incidence of cancer. The fruit of the Olea europaea L. and olive oil contain hundreds of phytochemicals and its extracts have recently been shown to exhibit antioxidant properties, due to the action of oleuropein. In view of these considerations, in this study, we investigated the effects of oleuropein on LNCaP and DU145 prostate cancer cell lines and on BPH-1 non-malignant cells. Oleuropein reduces cell viability and induces thiol group modifications, γ-glutamylcysteine synthetase, reactive oxygen species, pAkt and heme oxygenase-1. Exposing cell cultures to oleuropein induces an antioxidant effect on BPH-1 cells and a pro-oxidant effect on cancer cells. Our results confirm the beneficial properties of olive oil and oleuropein, suggesting its possible use as an adjuvant agent in the treatment of prostatitis, in order to prevent the transformation of hypertrophic to cancerous cells.

Novel phytonutrient contributors to antioxidant protection against cardiovascular disease.

The associations linking endothelial inflammation, endothelial oxidative stress, and atherogenesis and the potential for dietary phytonutrients to decrease the impact of these associations were assessed. A detailed literature review was conducted and summarized. A large body of scientific evidence describes the interactions among endothelial inflammation, endothelial oxidative stress, and atherogenesis. A growing body of research indicates that several dietary phytonutrients (astaxanthin, lycopene, lutein, and glabridin) can decrease the risk for atherosclerosis by decreasing endothelial inflammation and oxidative stress. The consumption of foods or dietary supplements that provide astaxanthin, lycopene, lutein, and glabridin can ameliorate endothelial inflammation and oxidative stress, retard atherogenesis, and decrease the risk for atherogenic cardiovascular disease.

Marine carotenoids and cardiovascular risk markers.

Marine carotenoids are important bioactive compounds with physiological activities related to prevention of degenerative diseases found principally in plants, with potential antioxidant biological properties deriving from their chemical structure and interaction with biological membranes. They are substances with very special and remarkable properties that no other groups of substances possess and that form the basis of their many, varied functions and actions in all kinds of living organisms. The potential beneficial effects of marine carotenoids have been studied particularly in astaxanthin and fucoxanthin as they are the major marine carotenoids. Both these two carotenoids show strong antioxidant activity attributed to quenching singlet oxygen and scavenging free radicals. The potential role of these carotenoids as dietary anti-oxidants has been suggested to be one of the main mechanisms for their preventive effects against cancer and inflammatory diseases. The aim of this short review is to examine the published studies concerning the use of the two marine carotenoids, astaxanthin and fucoxanthin, in the prevention of cardiovascular diseases.

Relationship between plasma antioxidant concentrations and carotid intima-media thickness: the Asymptomatic Carotid Atherosclerotic Disease In Manfredonia Study.

BACKGROUND: Few studies have examined the relationship among carotid atherosclerosis, vascular risk factors, and antioxidant plasma concentrations, and those that have reported conflicting results. The aim of this study was to assess the relationship between asymptomatic carotid atherosclerosis, as defined by carotid intima-media thickness (CIMT), and inflammatory markers, plasma lipids and serum antioxidant vitamins. METHODS AND RESULTS: We examined baseline characteristics of the 640 participants in the Asymptomatic Carotid Atherosclerotic Disease In Manfredonia Study. All participants were asymptomatic with respect to carotid artery disease in 2006-2007 and underwent physical examination with carotid ultrasound investigation, the collection of medical history and laboratory data. Analysis of variance methods were used to examine differences between participants by category of CIMT. Of the 640 participants, 291 did not have evidence of carotid atherosclerosis (CIMT<0.8 mm), 232 were found to have some atherosclerosis (0.8 mm< or =CIMT<1.2 mm), and 117 were found to have extensive atherosclerosis (CIMT>1.2 mm). Among participants with CIMT> or =0.8 mm, body mass index, blood pressures, total cholesterol, LDL cholesterol, triglycerides, uric acid, C-reactive protein, and fibrinogen were significantly higher, whereas concentrations of vitamin A, vitamin E, lycopene, and beta-carotene were all significantly lower when compared with participants who did not show evidence of carotid atherosclerosis (P<0.001). CONCLUSION: The optimal control of hypertension, diabetes, and dyslipidemia, in addition to smoking cessation and an adequate intake of antioxidant micronutrients from foods represent a key for the prevention of atherosclerotic disease.